Sotalol compositions and uses of the same

ABSTRACT

The present invention provides oral solutions containing sotalol hydrochloride which advantageously avoid swallowing while providing with improved stability. The present invention also relates to methods of using the oral solutions for treatment of diseases and disorders, such as delay in reoccurrence of atrial fibrillation/atrial flutter and/or ventricular arrhythmias.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/242,624, now U.S. Pat. No. 9,724,297, filed Apr. 1, 2014, thecontents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions containingsotalol hydrochloride, as well as methods of using such compositions totreat disease or disorders of the heart and methods of preparing suchcompositions.

BACKGROUND OF THE INVENTION

Sotalol hydrochloride is a non-selective competitive β-adrenergicreceptor blocker that also exhibits Class III antiarrhythmic propertiesby inhibiting potassium channels. Sotalol hydrochloride is currentlyindicated as a treatment for delay in recurrence of atrialfibrillation/atrial flutter and documented life-threatening ventriculararrhythmias. It is marketed in tablet form as Betapace and Betapace AF.

Some patients, such as children and the elderly, cannot swallow soliddosage forms. In order to provide sotalol hydrochloride to suchpatients, oral formulations must be prepared extemporaneously, typicallyat a compounding pharmacy. These oral formulations are suspensions andtypically containing 5 mg/mL of sotalol hydrochloride prepared bycompounding a Betapace AF tablet and simple syrup. Alternativeformulations are suspensions containing 5 mg/mL of sotalol hydrochlorideprepared by compounding Betapace with commercially available vehiclesincluding Ora-Plus (which contains microcrystalline cellulose, sodiumcarboxymethylcellulose, xanthan gum, carageenan, sodium phosphate andcitric acid), Ora-Sweet (which contains sucrose, glycerin, sorbitol,citrus-berry flavor, sodium phosphate and citric acid) and Ora-Sweet SF(which contains glycerin, sorbitol, sodium saccharin, xanthan gum,citrus-berry flavor, citric acid and sodium citrate) and are alsodescribed in Sidhom, M. B., et al., International Journal ofPharmaceutical Compounding, Vol. 9, No. 5, 2005, pp. 401-406.

Unfortunately, these extemporaneous oral suspensions have limitedstability, i.e., only three (3) months when stored at controlled roomtemperature and ambient humidity.

Accordingly, there remains a need for oral formulations of sotalolhydrochloride suitable for patients that cannot swallow solid dosagesthat have improved stability suitable for commercial sales.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions containingsotalol hydrochloride, as well as methods of using such compositions totreat diseases and disorders of the heart and methods of manufacture.The pharmaceutical compositions of the present invention are oralsolutions, which advantageously avoid difficulties in swallowing whileoffering improved stability.

In a first aspect, the present invention is an oral solution comprisingsotalol hydrochloride, wherein the solution is stable for greater than 4months.

In one embodiment, the oral solution is stable for greater than about 5months, about 6 months, about 8 months or about 12 months or longer.

In a particular embodiment, the oral solution comprises sotalolhydrochloride and water, and is stable for greater than about 4 months.

In another particular embodiment, the oral solution comprises sotalolhydrochloride and water, and is stable for greater than about 4 months,about 5 months, about 6 moths, about 8 months or about 12 months orlonger.

In another embodiment, the oral solution is substantially free ofpolymers.

In yet another embodiment, the oral solution has an osmolality in therange of about 20 mOsm/kg to about 400 mOsm/kg.

In a still further embodiment, the oral solution has a pH between about4.5 and about 5.5.

The oral solutions of the present invention may optionally containadditional excipients including buffers, preservatives, flavorings andhigh potency sweeteners.

In a particular embodiment, the oral solution consists of sotalolhydrochloride, water, citric acid, sodium citrate, sucralose, sodiumbenzoate and artificial grape flavor.

In another particular embodiment, the oral solution consists of sotalolhydrochloride, water, citric acid, sodium citrate, sucralose, sodiumbenzoate and artificial grape flavor, and is stable for greater thanabout 4 months, about 5 months, about 6 moths, about 8 months or about12 months or longer.

In a second aspect, the present invention is a method of treating adiseases and disorder comprising administering a therapeutically effectamount the oral solution of the present invention to a host in needthereof.

In one embodiment, the disease or disorder is a disease or disorder ofthe heart.

In a particular embodiment, the disorder is atrial fibrillation/atrialflutter.

In another embodiment, the disorder is a documented life-threateningventricular arrhythmias.

The therapeutically effective amount may vary, depending on thecharacteristics of the host and the severity of the disease or disorder.In a particular embodiment, the dose administered depends on the host'screative clearance.

In one embodiment, the host is administered a 80 mg daily dose of theoral solution.

In another embodiment, the host is administered a 160 mg daily dose ofthe oral solution.

In yet another embodiment, the host is administered a 360 mg daily doseof the oral solution.

In a particular embodiment, administration occurs once, twice or threetimes a day.

In one embodiment, the host is administered a 80 mg daily dose of theoral solution, once a day.

In another embodiment, the host is administered a 80 mg daily dose ofthe oral solution, once a day.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical compositions containingsotalol hydrochloride, as well as methods of using such compositions totreat disease and disorders of the heart (i.e., cardiac diseases anddisorders), and methods of preparing the same. The pharmaceuticalcompositions of the present invention are oral solutions and helppatients avoid difficulties in swallowing while offering improvedstability, particularly over extemporaneously prepared oral suspensionof sotalol hydrochloride known in the art.

I. Sotalol Hydrochloride

“Sotalol hydrochloride,” as used herein, refers tod,l-N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]phenyl]methane-sulfonamidemonohydrochloride. Both d- and l-isomers have similar Class IIIantiarrhythmic effects, while the 1-isomer is responsible for virtuallyall of the beta-blocking activity.

II. Pharmaceutical Compositions

The pharmaceutical compositions described herein are solutions, intendedfor oral administration. The oral solutions of the present invention areintended to provide safe and effective treatment for diseases anddisorders, including indications currently treated with the tablet formof sotalol hydrochloride.

The term “solution,” as used herein, refers to a homogenous mixture ofsubstances in the liquid phase. More particularly, solutes are dissolvedin the solvent (e.g. water) and do not separate out. The solutions ofthe present invention can be distinguished from suspensions, colloidsand dispersions by methods known to those of skill in the art. Forexample, particulates (solutes) in suspensions will eventually separate(e.g. oil in water). Colloids can be distinguished from solutions usingthe Tyndall effect.

The pharmaceutical compositions of the present invention are oralsolutions comprising sotalol hydrochloride and a solvent, i.e., sotalolhydrochloride dissolved in a solvent. The solvent may vary, and mayinclude purified water, distilled water, saline solution.

In one embodiment, the pharmaceutical composition is an oral solutioncomprising sotalol hydrochloride and water, to provide an aqueoussolution of sotalol hydrochloride.

In one embodiment, the pharmaceutical composition is an aqueous solutioncomprising sotalol hydrochloride and water, wherein water is present inan amount from about 95% to about 99% by weight, such as, for example,about 95%, about 96%, about 97%, about 98% or about 99%. In a moreparticular embodiment, water is present in an amount of about 98%.

The pharmaceutical compositions of the present invention have improvedstability, particularly compared to the extemporaneously prepared oralsuspensions known in the art. The term “stability,” as used herein,refers to compliance of the oral solution, at a given time point, withall of the “Shelf-life Specifications” provided in the Examples section.Specifically:

-   -   (i) the major (largest) peak in an HPLC trace of the solution        should correspond with a sotalol reference standard;    -   (ii) the UV spectrum of the main peak of the solution should        correspond with the a sotalol reference chromatogram;    -   (iii) sotalol should be present in 90.0% to 110.0% of        theoretical, as determined by CTMLP-3056 (analytical method for        impurities in sotalol oral solution; measured by HPLC);    -   (iv) not more than 0.2% related compound A (R,S        N[(4-[[(1-methylethyl)amino]acetyl]phenyl]methanesulfonamide        monohydrochloride; C₁₂H₁₈N₂O₃S.HCl, M.W.=306.81), not more than        0.2% related compound B (R,S        N-(4-formylphenyl)methanesulfonamide, C₈H₉NO₃S, M.W.=199.23),        not more than 0.2% related compound C (R,S        N-[4-[2-[(1-methylethyl)amino]ethyl]phenyl]methanesulfonamide        monohydrochloride, C₁₂H₂₀N₂O₂S.HCl, M.W.=292.83) and not more        than 2.5% total impurities;    -   (v) Sodium benzoate should be present in 80.0% to 110.0% of        theoretical, as determined by CTMLP-3057 (analytical assay of        sodium benzoate; measured by HPLC);    -   (vi) The pH is between 4.5 and 5.5;    -   (vii) Osmolality is less than 400 mOsm/kg; and    -   (viii) The solution should be a clear, colorless liquid by        visual inspection.

The pharmaceutical compositions of the present invention are oralsolutions comprising sotalol hydrochloride, stable under varied storageconditions for about 4 months or longer. More particularly, the aqueousoral solutions are stable for greater than about 5 months, greater thanabout 6 months, greater than about 8 months, greater than about 9months, greater than about 10 months, greater than about 11 months,greater than about 12 months, greater than about 13 months, greater thanabout 14 months, greater than about 15 months, greater than about 16months, greater than about 17 months, greater than about 18 months,greater than about 19 months, greater than about 20 months, greater thanabout 21 months, greater than about 22 months, greater than about 23months, greater than about 24 months or greater than about 36 months.

Storage conditions may vary, including by temperature and humidity.Storage may be under acid, neutral and alkaline conditions.

The temperature at which the oral solution is stored may vary. The oralsolution is preferably stored at a temperature between about 25° C. andabout 40° C. In a particular embodiment, the oral solution is stored atabout 25° C. In another particular embodiment, the oral solution isstored at about 30° C. In still another particular embodiment, the oralsolution is stored at about 40° C.

The relative humidity (RH) at which the oral solution is stored mayvary. The oral solution is preferably stored at an RH of between about60% and about 75%. In a particular embodiment, the oral solution isstored at about 60% RH. In another embodiment, the oral solution isstored at about 65% RH. In still another particular embodiment, the oralsolution is stored at about 75% RH.

In preferred embodiments, the oral solution is stored at a temperatureof between about 25° C. and about 40° C. and a RH of between about 60%and about 75% to provide maximum stability over time.

In certain embodiments, the present invention is an oral solutioncomprising sotalol hydrochloride stable for greater than about four (4)months when stored at about 25° C. and about 60% RH, about 30° C. andabout 65% RH or about 40° C. and about 75% RH. In a particularembodiment, the oral solution is stable for about five months, about sixmonths, about seven months, about eight months, about nine months, aboutten months, or about eleven months or longer.

In exemplary embodiments, the oral solution of the present invention isabout 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%,about 75%, about 80%, about 90%, about 95%, about 100% or more stablethan an oral suspension of sodium hydrochloride under the same storageconditions.

The amount of sotalol hydrochloride may vary. In one embodiment, sotalolhydrochloride is present in the oral solution in an amount from about 2mg/mL to about 8 mg/mL, such as, for example, about 2 mg/mL, about 3mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL orabout 8 mg/mL.

In a particular embodiment, the pharmaceutical composition is an oralsolution comprising about 5 mg/ml of sotalol hydrochloride.

Sotalol hydrochloride can be present in the oral solutions of thepresent invention in an amount from about 0.2% to about 0.8% by weight,such as, for example, about 0.2%, about 0.3%, about 0.4%, about 0.5%,about 0.6%, about 0.7% or about 0.8%.

In a particular embodiment, the pharmaceutical composition is an oralsolution comprising about 0.5% by weight sotalol hydrochloride.

In certain embodiments, the pharmaceutical composition of the presentinvention is an oral solution of sotalol hydrochloride that does notcontain polymers, or more particularly, does not contain polymers thatcontribute to stabilization or emulsification, for examplepolysaccharide polymers. In an exemplary embodiment, the pharmaceuticalcomposition is an oral solution of sotalol hydrochloride that does notcontain polysaccharide polymers, such as xanthan gum.

The osmolality of the oral solution may vary. In one embodiment, theoral solution has an osmolality in the range of about 20 mOsm/kg toabout 400 mOsm/kg, such as, for example, from about 50 to about 300mOsm/kg, from about 100 to about 200 mOsm/kg, from about 50 to about 100mOsm/kg or about 200 to about 350 mOsm/kg. In a particular embodiment,the osmolality of the oral solution is from about 200 to about 300mOsm/kg, more particularly from about 200 to about 250 mOsm/kg.

The pH of the oral solutions may range from about 3 to about 7 andprovide osmolalities in the range of about 20 mOsm/kg to about 350mOsm/kg. pHs from about 4 to about 6 are preferred, with pHs from about4.5 to 5.5 more preferred, such as, for example, about 4.5, about 4.6,about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about5.3, about 5.4 and about 5.5.

The oral solutions of the present invention may optionally compriseother excipients. The solutions may contain, inter alia, acids, bases orbuffer substances for adjusting the pH, e.g., citric acid, sodiumcitrate, phosphoric acid, sodium phosphate as well as mixtures ofcitrate and phosphate buffers; preservatives, e.g., sulfites (sulfurdioxide, sodium bisulfite, and potassium hydrogen sulfite), propionates(propionic acid, calcium propionate, and sodium propionate), benzoates(sodium benzoate, and benzoic acid), sorbates (potassium sorbate, sodiumsorbate, calcium sorbate, and sorbic acid), nitrates (sodium nitrate),nitrites (sodium nitrite) and methyl paraben; high potency sweeteners,e.g. sucralose, potassium acesulfame, acesulfame acid and salts thereof,aspartame, alitame, saccharin and salts thereof, neohesperidindihydrochalcone, cyclamate, cyclamic acid and salts thereof, neotame,advantame, glucosylated steviol glycosides (GSGs) and combinationsthereof, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D,rebaudioside E, rebaudioside F, rebaudioside I, rebaudioside H,rebaudioside L, rebaudioside K, rebaudioside J, rebaudioside M,rebaudioside N, rebaudioside O, dulcoside A, dulcoside B, rubusoside,stevia, stevioside, mogroside IV, mogroside V, Luo Han Guo sweetener,siamenoside, monatin and its salts (monatin SS, RR, RS, SR), curculin,glycyrrhizic acid and its salts, thaumatin, monellin, mabinlin,brazzein, hemandulcin, phyllodulcin, glycyphyllin, phloridzin,trilobatin, baiyunoside, osladin, polypodoside A, pterocaryoside A,pterocaryoside B, mukurozioside, phlomisoside I, periandrin I,abrusoside A, steviolbioside and cyclocarioside I; and flavoring agents,e.g. peppermint oil, spearmint oil, other mint oils, clove oil, cinnamonoil, oil of wintergreen, bay, thyme, cedar leaf, nutmeg, allspice, sage,mace, almonds, apple, banana, watermelon, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot, lemon, lime,orange, tangerine, grapefruit, citron, or kumquat. Natural or artificialflavoring agents can be used.

In one embodiment, the oral solution further comprises bufferingsubstances in an amount from about 0.5% to about 1.5%, by weight suchas, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4% orabout 1.5%. In a more particular embodiment, the buffering substancesare sodium citrate and citric acid in an amount of about 0.9%.

In another embodiment, the oral solution further comprises at least onepreservative in an amount from about 0.10% to about 0.50% by weight,such as, for example, about 0.10%, about 0.15%, about 0.20%, about0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45% or about0.50%. In a more particular embodiment, the preservative is sodiumbenzoate in an amount of about 0.25%.

In still another embodiment, the oral solution further comprises atleast one high potency sweetener from about 0.010% to about 0.050% byweight, such as, for example, about 0.010%, about 0.015%, about 0.020%,about 0.025%, about 0.030%, about 0.035%, about 0.040%, about 0.045% orabout 0.050%. In a more particular embodiment, the high potencysweetener is sucralose in an amount of about 0.025%.

In yet another embodiment, the oral solution further comprises at leastone flavor ingredient in an amount from about 0.10% to about 0.50% byweight, such as, for example, about 0.10%, about 0.15%, about 0.20%,about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45% or about0.50%. In a more particular embodiment, the flavor ingredient isartificial grape flavor in an amount of about 0.25%.

In a particular embodiment, the oral solution comprises water in anamount of about 95% to about 99% by weight, sotalol hydrochloride in anamount from about 0.2% to about 8% by weight, at least one bufferingsubstance, at least one preservative, and optionally, at least one highpotency sweetener and at least one flavor ingredient.

In a particular embodiment, the oral solution comprises water in anamount of about 95% to about 99%, sotalol hydrochloride in an amountfrom about 0.2% to about 8%, buffering substances in an amount fromabout 0.5% to about 1.5%, at least one preservative in an amount fromabout 0.10% to about 0.50%, at least one high potency sweetener fromabout 0.010% to about 0.050% and at least one flavor ingredient in anamount from about 0.10% to about 0.50%. All percentages are given byweight.

In another particular embodiment, an oral solution comprises water in anamount of about 95% to about 99%, sotalol hydrochloride in an amountfrom about 0.2% to about 8%, sodium citrate and citric acid in an amountfrom about 0.5% to about 1.5%, sodium benzoate in an amount from about0.10% to about 0.50%, sucralose in an amount from about 0.010% to about0.050% and artificial grape flavor in an amount from about 0.10% toabout 0.50%. All percentages are given my weight.

In yet another particular embodiment, the oral solution comprises waterin an amount of about 98%, sotalol hydrochloride in an amount of about0.5%, sodium citrate and citric acid in an amount of about 0.9%, sodiumbenzoate in an amount of about 0.25%, sucralose in an amount of about0.025% and artificial grape flavor in an amount of about 0.25%. Allpercentages are given by weight.

III. Methods of Use

The present invention also provides for methods of treating a disease ordisorder comprising administering the oral solutions of the presentinvention to a host in need thereof.

As used herein, “treatment” or “treat” means any treatment of a diseaseor disorder in a host such as a mammal, including: (a) protectingagainst the disease or disorder, that is, causing the clinical symptomsnot to develop; (b) inhibiting the disease or disorder, that is,arresting, ameliorating, reducing, or suppressing the development ofclinical symptoms; and/or (c) relieving the disease or disorder, thatis, causing the regression of clinical symptoms. It will be understoodby those skilled in the art that in human medicine, it is not alwayspossible to distinguish between “preventing” and “suppressing” since theultimate inductive event or events may be unknown, latent, or thepatient is not ascertained until well after the occurrence of the eventor events. Therefore, as used herein the term “prophylaxis” is intendedas an element of “treatment” to encompass both “preventing” and“suppressing” as defined herein. The term “protection,” as used herein,is meant to include “prophylaxis.”

The host may be, for example, any living mammal in need or likely inneed of treatment, including primates, in particular humans, and othermammals such as, for example, equines, cattle, swine, sheep, felines,canines, poultry and domestic pets in general. In a particularembodiment, the patient is a human, more particularly a human unable toswallow tablets, e.g. children and/or the elderly.

Such methods of treatment would have particular utility in numeroustherapeutic settings (as well as others which may be determined bysomeone skilled in the art) including, but not limited to treatment ofdiseases or disorders of the heart, including but not limited:

i) Acute control and prevention of the recurrences of life-threateningdisorders of rhythm such as ventricular tachycardia and ventricularfibrillation occurring in patients with coronary artery disease;

ii) Prevention of defibrillator shocks in patients with implantabledevices for the prevention of sudden death;

iii) Termination and prevention of recurrences of atrial fibrillationand flutter in patients;

iv) Prevention of the occurrences of atrial fibrillation by prophylacticadministration;

v) Symptomatic control of angina pectoris in patients still experiencingchest pain after cardiac surgery, after myocardial infarction, orpatients with coronary artery disease not amenable to treatment bysurgery or angioplasty;

vi) Control of systemic systolic and diastolic high blood pressure;

vii) Adjunctive therapy for the control of heart rate and atrialfibrillation in the initial acute stages of hyperthyroidism;

viii) Control of atrial fibrillation, myocardial ischemia in the settingof ischemic heart disease, and hypertension simultaneously occurring;

ix) Control of fetal tachycardias; and

x) Other uses of sotalol hydrochloride that have therapeutic activityfor any purpose.

In a particular embodiment, the present invention is a method fordelaying recurrence of atrial fibrillation/atrial flutter comprisingadministering an oral solution of the present invention to a host inneed thereof.

In another particular embodiment, the present invention is a method fortreating documented life-threatening ventricular arrhythmias comprisesadministering an oral solution of the present invention to a host inneed thereof.

The dosing protocol can be determined by a physician or otherappropriate treatment supervisor in light of the relevant circumstancesincluding, for example, age, weight, response of the individual patient,severity of the patient's symptoms and/or creatine clearance ability.Patients should of course be monitored for possible adverse events.

In one embodiment, the dose of the oral solution administered isbioequivalent to about sotalol hydrochloride in pill form. In apreferred embodiment, dosing of an oral solution of the presentinvention is consistent with dosing for commercially available Betapace.

In one embodiment, the host is administered a 80 mg daily dose, a 100 mgdaily dose, a 120 mg daily dose, a 140 mg daily dose, a 160 mg dailydose, a 180 mg daily dose, a 200 mg daily dose, a 220 mg daily dose, a240 mg daily dose, a 260 mg daily dose, a 280 mg daily dose, a 300 mgdaily dose, a 320 mg daily dose, a 340 mg daily dose or a 360 mg dailydose of the oral solution.

Administration of the oral solution may occur once, twice or three timesa day.

In one embodiment, the host is administered an 80 mg daily dose of theoral solution, once a day.

In another embodiment, the host is administered an 80 mg daily dose ofthe oral solution, once a day.

In one embodiment, the method comprises administering the oral solutionto a host in need thereof in an initial oral dose of about 80 mg, onceor twice daily, based on creatine clearance.

In a particular embodiment, the oral solution is administered in aninitial dose of about 80 mg twice a day to a host in need thereof with acreatine clearance greater than 60 mL/min.

In another particular embodiment, the oral solution is administered inan initial dose of about 80 mg once a day in a host in need thereof witha creatine clearance between 40 and 60 mL/min.

In exemplary embodiments, the dose is increased up to 320 mg once ortwice a day, depending on creatine clearance, if the 80 mg dose does noteffectively provide treatment for the host to which it was administered(e.g., the 80 mg treatment does not reduce frequency of life-threateningdisorders of rhythm such as ventricular tachycardia or reducesymptomatic atrial fibrillation and flutter).

In a particular embodiment, the dose may be increased in increments of80 mg per day for three days. QTc should be monitored during doseescalation.

In some embodiments, the oral solution is administered in a dose up to160 mg one or twice a day to a host in need thereof.

In other embodiments, the oral solution is administered in a dose up to240 mg one or twice a day to a host in need thereof.

In still further embodiments, the oral solution is administered in adose up to 320 mg once or twice a day to a host in need thereof.

In one embodiment, the host in need thereof is a child aged about 2years or older, with normal renal function, and the dose administered isnormalized for body surface area for both initial and incrementaldosing. Since the Class III potency in children is not very differentfrom that in adults, reaching plasma concentrations that occur withinthe adult dose range is an appropriate guide. In a particularembodiment, the oral solution is administered in an initial dose ofabout 30 mg/m² three times a day (90 mg/m² total daily dose). This doseis approximately equivalent to an initial 160 mg total daily dose foradults. Subsequent titration to a maximum of 60 mg/m² (approximatelyequivalent to the 360 mg total daily dose for adults) can then occur.Titration should be guided by clinical response, heart rate and QTc,with increased dosing being preferably carried out in-hospital. At least36 hours should be allowed between dose increments to attainsteady-state plasma concentrations of sotalol in patients withage-adjusted normal renal function.

For children aged about 2 years or younger, the above pediatric dosagemay be reduced by a factor that depends heavily upon age.

In one embodiment, the dose for a child aged 20 months is the dosesuggested for children with normal renal function aged 2 years orgreater multiplied by about 0.97; the initial starting dose would be(30×0.97)=29.1 mg/m², administered three times daily.

In another embodiment, the dose for a child aged 1 month, the startingdose should be multiplied by 0.68; the initial starting dose would be(30×0.68)=20 mg/m², administered three times daily.

For a child aged about 1 week, the initial starting dose should bemultiplied by 0.3; the starting dose would be (30×0.3)=9 mg/m². Similarcalculations should be made for increased doses as titration proceeds.

The oral solution may be administered before, together with, or afterintake of food.

IV. Methods of Preparation

The present invention also extends to methods of preparing ormanufacturing the oral solutions of the present invention.

In one embodiment, the method of preparation comprises admixing byadmixing sotalol hydrochloride with water.

In a particular embodiment, the method of preparation comprises admixingsotalol hydrochloride and one or more excipients with water.

The oral solution of the present invention is prepared by completelydissolving the sotalol hydrochloride and optionally the excipients, insolution.

An exemplary embodiment of the method of preparation is provided inExample 1, hereto.

EXAMPLES Example 1: Oral Sotalol Solution and Preparation of the Same

Material % w/w Purified Water 98.075 Citric Acid Monohydrate 0.260Sodium Citrate Dihydrate 0.640 Sucralose 0.025 Sodium Benzoate 0.250Sotalol HCl 0.500 Artificial Grape Flavor 0.250

Manufacturing Process for Sotalol Hydrochloride Oral Solution (5 mg/mL)

Purified Water to the amount of 75% of the formulation (525 kg) wasadded to a 2300 L stainless steel mixing tank equipped with a variablespeed mixer. The mixer was set at a speed to maintain a vortex. The rawmaterials were added to the batch in the order listed in the tableabove. Each material was added separately and mixed until dissolved. Thetemperature and mixing time for each addition was recorded. Once all ofthe raw materials were added, the batch was brought to a final targetweight of 700 kg with purified water and mixed. The batch was thenpassed through an in-line filter housing equipped with a 10 μm cartridgefilter into a holding tank. The specific gravity, pH, and final batchyield of each batch was determined. A summary of the manufacturingprocess and process parameters is outlined below:

Summary of Manufacturing Steps and Process Parameters for theManufacture of Sotalol Hydrochloride Oral Solution 5 mg/mL ManufacturingStep MFYN MFYP MFYS Charge Purified Water to 2300L Mixing 22.9 22.9 22.2Tank, record temperature (° C.) Set variable speed mixer to maintain 280285 280 vortex (rpm) Charge Citric Acid Monohydrate and mix untildissolved, Mixing Time (min) 10 10 10 Temperature (′C.) 21.2 22.4 20.6Charge Sodium Citrate Dihydrate and mix until dissolved Mixing Time(min) 10 10 10 Temperature (′C.) 20.5 22.2 20.5 Charge Sucralose and mixuntil dissolved, Mixing Time (nun) 10 10 10 Temperature (° C.) 17.7 22.616.6 Charge Sodium Benzoate and mix until dissolved, Mixing Time (min)10 10 10 Temperature (° C.) 20.5 22.4 19.8 Charge Sotalol HydrochlorideUSP and mix until dissolved, Mixing Time (min) 10 10 10 Temperature (°C.) 21.0 22.1 20.9 Charge Grape Flavor and mix until dissolved, MixingTime (min) 10 10 10 Temperature (° C.) 21.3 22.1 21.2 Determine Net Wt.Of solution (kg) 539.0 534.0 536.5 Adjust the batch weight to target of700.0 kg with Purified Water Amount of Purified Water to q.s. 161.0166.0 163.5 Mix for additional 10 minutes Mixing Time (min) 10 10 10Temperature (° C.) 21.4 22.3 20.6 Mixing Speed (rpm) 280 285 280Determine Specific Gravity of Solution 1.008 1.008 1.010 Determine pH ofSolution pH 5.00 4.98 5.04 Temperature (° C.) 24.2 24.4 23.6 Using thepump, transfer solution to holding tank through in-line filter housingwith 10 μm cartridge filter Final Batch Weight after transfer (kg) 696.6698.4 697.2 Convert batch size to litres (L) 691.1 692.9 690.3 SampleWeight (kg) 0.7 0.7 0.7

Example 2: Preparation of Sotalol Extemporaneous Suspension

The extemporaneous suspension was prepared according to the labeling forthe commercially available sotalol hydrochloride tablets, i.e. 5 tablets(120 mg each) were added to 120 mL of Simple Syrup with 0.1% sodiumbenzoate (Syrup N.F.) in an oversized (180 mL) plastic (PET)prescription bottle. The tablets were allowed to hydrate for at least 2hours, then shaken intermittently over the course of at least another 2hours until the tablets were completely disintegrated. A dispersion offine particles was obtained. The tablets were then allowed to hydrateovernight to simplify disintegration process. The resulting preparationcontains 5 mg/mL of sotalol hydrochloride in solution with suspendedinactive solid particles (water˜insoluble tablet ingredients).

Example 3: pH and Osmolality of Standard Preparations

The pH and osmolality for the solution in Example 1 and the suspensionin Example 2 were determined:

Osmolality Undiluted Sample pH (mOsm/kg) Sotalol HCl Oral Solution(Example 1) 5.1 212 Sotalol HCl Tablets in H₂O 5.4 39 SotalolExtemporaneous Suspension (Example 2) 2.4 2680

The results showed that the osmolality for the sotalol HCl solution(Example 1) falls within range of the osmolality for the marketedSotalol HCl tablet and the osmolality of the extemporaneously preparedsuspension. Likewise, the pH for the sotalol HCl solution falls withinrange of the pH for the marketed Sotalol HCl tablet and the pH of theextemporaneously prepared suspension. Notable differences were found inpH and osmolality between the oral solution and the extemporaneoussuspension.

Example 4: pH and Osmolality of Diluted Preparations

Dilutions of 80 mg (16 mL) doses of the Sotalol HClsolutions/suspensions were made with diluents of different pH. The pHand Osmolality results for the diluted Sotalol preparations are shown inthe table below.

Sotalol Sotalol Sotalol HCl HCl Extemporaneous tablets pH OsmolalitySolution pH Osmolality Suspension pH Osmolality A 4.5 291 A 4.5 318 A4.5 843 B 7.0 94 B 6.7 118 B 6.9 603 C 1.7 73 C 1.9 84 C 1.5 601 D 5.6 4D 5.6 26 D 4.1 517 A: For tablets: Sotalol HCl tablets in DI water,diluted with pH 4.5 acetate buffer; For Sotalol HCl solution andsuspension: diluted with pH 4.5 acetate buffer B: For tablets: SotalolHCl tablets in DI water, diluted with pH 6.8 phosphate buffer; ForSotalol HCl solution and suspension: diluted with pH 6.8 phosphatebuffer C: For tablets: Sotalol HCl tablets in DI water, diluted withpH~1 HCl; For Sotalol HCl solution and suspension: diluted with pH~1 HClD: For tablets: Sotalol HCl tablets in DI water, diluted with DI water;For Sotalol HCl solution and suspension: diluted with DI water

The results of this assessment showed that the osmolality for thesotalol HCl solution in different pH dilutions falls within range of theosmolality values for the marketed Sotalol HCl tablet and the osmolalityvalues of the extemporaneously prepared suspension.

Example 5: Stability Studies of Sotalol Hydrochloride Oral Solution (5mg/mL)

Stability data up to 11 months at 25° C./60% relative humidity (RH) and30° C./65% RH and up to 6 months at 40° C./75% RH for three registrationbatches of Sotalol Hydrochloride Oral Solution (batches MFYN, MFYP, andMFYS), representing the commercial process and manufactured at theintended commercial supplier.

The three batches were packed in 250 mL and 480 mL bottles, representingsix packaging batches. Sotalol Hydrochloride Oral Solution was packagedas a 250 mL product in a 250 mL, round, amber PET bottle with a 24 mmwhite HDPE child resistant cap with an induction seal. The product wasalso packaged as a 480 mL product in a 500 mL, round, amber, PET bottlewith a 28 mm white HDPE child resistant cap with an induction seal.Photostability testing was performed on batch MFYN (packaged batchesMHBV and MHBP) in compliance with International Conference onHarmonization (ICH) recommended storage conditions. Batches were storedin accordance with the following ICH conditions. The bottles were storedin the inverted and upright position.

Drug Product Stability Storage Conditions Storage Condition Description25° C./60% RH 25° C. ± 2° C./60% ± 5% Relative Humidity (RH) 40° C./75%RH 40° C. ± 2° C./75% ± 5% Relative Humidity (RH) 30° C./65% RH 30° C. ±2° C./76% ± 5% Relative Humidity (RH) Photostability ICH Q1B, Option 2

Stability Protocol for Sotalol Hydrochloride Oral Solution in 250 mL and480 mL Bottles Time point (months) 0^(a) 1^(b) 3 6^(d) 8^(c,d) 9^(d)11^(c,d) 12^(d,e) 18 24^(c) 36^(c) Packaging 250 mL MHBS T T T T T T T TT T Configuration (upright) MHBT T T T T T T T T T T MHBP T T T T T T TT T 480 mL MHBW T T T T T T T T T (upright) MHBX T T T T T T T T T TMHBV T T T T T T T T T Packaging 250 mL MHBS T T T T T T T T TConfiguration (inverted) MHBT T T T T T T T T T MHBP T T T T T T T T T T480 mL MHBW T T T T T T T T T T (inverted) MHBX T T T T T T T T T MHBV TT T T T T T T T T Key: T = Samples will be tested at all temperaturesunless noted otherwise (appearance, appearance of packaging, pH,osmolality, sodium benzoate assay, sotalol HCl assay, relatedsubstances) ^(a)ID and specific gravity only tested at T = 0 ^(b)40°C./75% RH testing only ^(c)includes micro and AET testing ^(d)includes30° C./65% RH testing ^(e)includes micro testing Water loss is onlyconducted at 25° C./60% RH

The results of these studies are shown in the tables that follow. Theabbreviations have the following meanings:

NR = Not required TAMC = Total aerobic microbial count ND = Not detectedTYCM = Total combined yeasts and molds count

TABLE 1 Stability of 250 mL at 25° C./60% RH 3 month 6 month 8 month 9month^(a) 11 month Initial Upright Inverted Upright Inverted UprightInverted Inverted Upright Inverted Date Apr. 4, 2013 Jul. 9, Jul. 9,Oct. 4, Oct. 4, Dec. 2, 2013 Dec. 2, 2013 Jan. 9, Feb. 28, Feb. 28, 2014Samples 2013 2013 2013 2013 2014 2014 Pulled Appearance Clear, colorlessComplies Complies Complies Complies Complies Complies Complies CompliesComplies Complies liquid Appearance 250 mL, amber Complies CompliesComplies Complies Complies Complies Complies Complies Complies Compliesof PET round Packaging bottle; white child resistant cap with inductionseal. No visible damage to any of the components Identification Exhibitsmajor Complies NR NR NR NR NR NR NR NR NR of Sotalol peak for Sotalol;HCl by Retention time HPLC is the same as that of the reference standardIdentification The spectrum of Complies NR NR NR NR NR NR NR NR NR ofSotalol the main peak in HCl by UV the sample chromatogram matches thespectrum of the main peak in the standard chromatogram Assay for90.0%-110.0% 1) 101.9% 1) 99.7% 1) 99.7% 1) 1) 1) 101.0% 1) 102.6% 1)101.3% 1) 1) 101.7% Sotalol HCl of theoretical 2) 101.6% 2) 99.7% 2)99.8% 101.3% 101.7% 2) 102.6% 2) 101.4% 2) 101.7% 102.3% 2) 102.0% Mean:Mean: Mean: 2) 2) Mean: Mean: Mean: 2) Mean: 101.9% 101.8% 99.7% 99.8%101.5% 101.9% 101.8% 102.0% 101.5% 102.3% Mean: Mean: Mean: 101.4%101.8% 102.3% Related Related ND ND ND ND ND ND ND ND ND ND SubstancesCompound A: NMT 0.2% Related ND ND ND ND ND ND ND ND <QL ND Compound B:NMT 0.2% Related ND ND ND ND ND ND ND ND ND ND Compound C: NMT 0.2%Unknown RRT 0.74: ND ND <QL <QL RRT 2.16: <QL RRT 2.17: <QL RRT 2.10:RRT 2.12: RRT 2.12: <QL Impurities: 0.10% RRT 2.75: 0.05 RRT 2.77: 0.050.05 <QL RRT 2.83: 0.09% NMT 0.1% RRT 2.12: RRT 3.67: <QL RRT 3.70: <QLRRT 2.61: RRT 2.84: 0.05% 0.06 0.09% Total 0.15% ND ND <QL <QL 0.05%0.05% 0.11% 0.09% 0.09% Impurities: NMT 2.5% Assay of 80.0-110.0% of 1)100.4% 1) 1) 1) 1) 1) 101.1% 1) 101.1% 1) 101.0% 1) 1) 100.7% Sodiumtheoretical 2) 100.5% 101.2% 102.5% 102.1% 101.0% 2) 100.6% 2) 101.1% 2)100.8% 100.6% 2) 100.9% Benzoate Mean: 2) 2) 2) 2) Mean: Mean: Mean: 2)Mean: 100.8% 100.5% 101.9% 102.4% 102.5% 101.8% 100.9% 101.1% 100.9%100.8% Mean: Mean: Mean: Mean: Mean: 101.6% 102.5% 102.3% 101.4% 100.7%pH 4.5-5.5 5.05 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Osmolality ≤400mOsm/kg 182 mOsm/kg 181 mOsm/kg 183 mOsm/kg 184 mOsm/kg 184 mOsm/kg 182mOsm/kg 183 mOsm/kg 184 mOsm/kg 187 mOsm/kg 187 mOsm/kg Specific Reportresult 1.0077 NR NR NR NR NR NR NR NR NR Gravity Microbial TAMC: NMT <10cfu/mL NR NR NR NR <10 cfu/mL <10 cfu/mL NR <10 cfu/mL <10 cfu/mL Limits10² cfu/mL TCYM: NMT <10 cfu/mL <10 cfu/mL <10 cfu/mL <10 cfu/mL <10cfu/mL 10¹ cfu/mL E. Coli: Absent/mL Absent/mL Absent/mL Absent/mLAbsent/mL Absence/mL S. aureus: Absent/mL Absent/mL Absent/mL Absent/mLAbsent/mL Absence/mL P. aeruginosa: Absent/mL Absent/mL Absent/mLAbsent/mL Absent/mL Absence/mL Salmonella: Absent/10 mL Absent/10 mLAbsent/10 mL Absent/10 mL Absent/10 mL Absence/10 mL B. cepacia:Absent/mL Absent/mL Absent/mL Absent/mL Absent/mL Absence/mL AET MeetsPass NR NR NR NR Pass Pass NR Pending Pending acceptance criteria statedin USP<51> Water Loss Report result NR Mean: Mean: Mean: Mean: Mean:Mean: Mean: Mean: Mean: 1.0335% 0.2735% 0.2739% 0.5595% 0.5781% 0.7467%0.7444% 0.8719% 1.0290% ^(a)Alternate orientation not required due tostability matrixing

TABLE 2 Stability of 480 mL at 25° C./60% RH 3 month 6 month 8 month 9month^(a) 11 month Initial Upright Inverted Upright Inverted UprightInverted Inverted Upright Inverted Date Apr. 4, 2013 Jul. 9, Jul. 9,2013 Oct. 4, Oct. 4, Dec. 2, 2013 Dec. 2, 2013 Jan. 9, Feb. 28, 2014Feb. 28, Samples 2013 2013 2013 2014 2014 Pulled Appearance Clear,colorless Complies Complies Complies Complies Complies Complies CompliesComplies Complies Complies liquid Appearance 480 mL, amber PET CompliesComplies Complies Complies Complies Complies Complies Complies CompliesComplies of round bottle; white Packaging child resistant cap withinduction seal. No visible damage to any of the componentsIdentification Exhibits major peak Complies NR NR NR NR NR NR NR NR NRof Sotalol for Sotalol; HCl by Retention time is HPLC the same as thatof the reference standard Identification The spectrum of the Complies NRNR NR NR NR NR NR NR NR of Sotalol main peak in the HCl by UV samplechromatogram matches the spectrum of the main peak in the standardchromatogram Assay for 90.0%-110.0% of 1) 101.0% 1) 101.3% 1) 101.0% 1)102.4% 1) 102.3% 1) 102.3% 1) 102.4% 1) 1) 102.0% 1) 101.7% Sotalol HCltheoretical 2) 102.1% 2) 101.5% 2) 101.4% 2) 102.5% 2) 102.2% 2) 103.3%2) 103.8% 101.6% 2) 102.1% 2) 101.9% Mean: Mean: Mean: Mean: Mean: Mean:Mean: 2) Mean: Mean: 101.6% 101.4% 101.2% 102.5% 102.3% 102.8% 103.1%100.9% 102.1% 101.8% Mean: 101.3% Related Related Compound ND ND ND NDND ND ND ND ND ND Substances A: NMT 0.2% Related Compound ND ND ND ND NDND ND ND <QL <QL B: NMT 0.2% Related Compound ND ND ND ND ND ND ND ND NDND C: NMT 0.2% Unknown RRT 0.74: RRT 0.78: RRT 0.78: <QL <QL RRT 2.16:<QL RRT 2.22: <QL RRT 2.09: RRT 2.13: RRT 2.14: Impurities: NMT 0.14%<QL 0.05% RRT 2.75: <QL RRT 2.82: <QL <QL 0.06% 0.06% 0.1% RRT 2.12: <QLRRT 2.04: RRT 2.04: <QL RRT 3.45: <QL RRT 2.60: RRT 2.63: <QL RRT 2.91:<QL 0.06% RRT 2.92: 0.08% 0.08% Total Impurities: 0.14% <QL 0.05% <QL<QL <QL <QL 0.06% 0.09% 0.14% NMT 2.5% Assay of 80.0-110.0% of 1)100.0% 1) 101.7% 1) 101.5% 1) 101.5% 1) 102.6% 1) 101.0% 1) 100.9% 1) 1)100.4% 1) 100.6% Sodium theoretical 2) 99.9% 2) 102.4% 2) 101.4% 2)102.1% 2) 102.0% 2) 100.9% 2) 101.1% 101.1% 2) 100.3% 2) 100.5% BenzoateMean: Mean: Mean: Mean: Mean: Mean: Mean: 2) Mean: Mean: 100.0% 102.1%101.5% 101.8% 102.3% 101.0% 101.0% 101.7% 100.4% 100.6% Mean: 101.4% pH4.5-5.5 5.06 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Osmolality ≤400 mOsm/kg182 mOsm/kg 183 mOsm/kg 182 mOsm/kg 182 mOsm/kg 184 mOsm/kg 183 mOsm/kg183 mOsm/kg 183 mOsm/kg 187 mOsm/kg 185 mOsm/kg Specific Report result1.0076 NR NR NR NR NR NR NR NR NR Gravity Microbial TAMC: <10 cfu/mL NRNR NR NR <10 cfu/mL <10 cfu/mL NR <10 cfu/mL <10 cfu/mL Limits NMT 10²cfu/mL TCYM: <10 cfu/mL <10 cfu/mL <10 cfu/mL <10 cfu/mL <10 cfu/mL NMT10¹ cfu/mL E. Coli: Absent/mL Absent/mL Absent/mL Absent/mL Absent/mLAbsence/mL S. aureus: Absent/mL Absent/mL Absent/mL Absent/mL Absent/mLAbsence/mL P. aeruginosa: Absent/mL Absent/mL Absent/mL Absent/mLAbsent/mL Absence/mL Salmonella: Absent/10 mL Absent/10 mL Absent/10 mLAbsent/10 mL Absent/10 mL Absence/10 mL B. cepacia: Absent/mL Absent/mLAbsent/mL Absent/mL Absent/mL Absence/mL AET Meets acceptance Pass NR NRNR NR Pass Pass NR Pending Pending criteria stated in USP<51> Water LossReport result NR Mean: Mean: Mean: Mean: Mean: Mean: Mean: Mean: Mean:0.2875% 0.3813%* 0.5618% 0.7028%* 0.7311% 0.9449%* 1.0987%* 1.0167%1.2630%* ^(a)Alternate orientation not required due to stabilitymatrixing *OOS64084 for an individual water loss due to leaking bottle#1

TABLE 3 Stability of 250 mL at 30° C./65% RH 6 month 8 month 9 month 11month Initial Upright Inverted Upright Upright Upright Inverted UprightInverted Date Apr. 4, 2013 Oct. 4, Oct. 4, 2013 Dec. 2, 2013 Feb. 28,2014 Jan. 9, 2014 Jan. 9, 2014 Feb. 28, 2014 Feb. 28, 2014 Samples 2013Pulled Appearance Clear, colorless Complies Complies Complies CompliesComplies Complies Complies Complies Complies liquid Appearance 250 mL,amber Complies Complies Complies Complies Complies Complies CompliesComplies Complies of Packaging PET round bottle; white child resistantcap with induction seal. No visible damage to any of the componentsIdentification Exhibits major Complies NR NR NR NR NR NR NR NR ofSotalol peak for Sotalol; HCl by Retention time is HPLC the same as thatof the reference standard Identification The spectrum of the Complies NRNR NR NR NR NR NR NR of Sotalol main peak in the HCl by UV samplechromatogram matches the spectrum of the main peak in the standardchromatogram Assay for 90.0%-110.0% of 1) 101.9% 1) 100.5% 1) 100.6% 1)101.0% 1) 101.8% 1) 101.5% 1) 100.6% 1) 101.8% 1) 101.8% Sotalol HCltheoretical 2) 101.6% 2) 100.4% 2) 100.3% 2) 101.5% 2) 102.1% 2) 101.6%2) 101.6% 2) 102.1% 2) 101.9% Mean: Mean: Mean: Mean: Mean: Mean: Mean:Mean: 102.0% Mean: 101.9% 101.8% 100.5% 100.5% 101.3% 102.0% 101.6%101.1% Related Related Compound ND ND ND ND ND ND ND ND ND Substances ANMT 0.2% Related Compound ND ND ND ND ND ND ND ND ND B NMT 0.2% RelatedCompound ND ND ND ND ND ND ND ND ND C NMT 0.2% Unknown RRT 0.74: <QL RRT2.05: RRT 2.76: RRT 2.12: <QL RRT 2.10: 0.05% RRT 2.10: RRT 2.12: <QLRRT 2.12: <QL Impurities NMT 0.10% 0.06% 0.11% RRT 2.83: RRT 2.62: 0.13%0.05% RRT 2.83: 0.17%* RRT 2.84: 0.17%* 0.1% RRT 2.12: RRT 2.10: RRT3.69: <QL 0.17%* RRT 2.72: <QL RRT 2.61: RRT 2.95: <QL RRT 2.96: <QL0.05% 0.05% RRT 2.95: <QL 0.13% RRT 2.66: RRT 2.71: <QL 0.10% TotalImpurities: 0.15% <QL 0.21% 0.11% 0.17% 0.18% 0.18% 0.17% 0.17% NMT 2.5%Assay of 80.0-110.0% of 1) 100.4% 1) 101.8% 1) 102.1% 1) 101.4% 1)101.1% 1) 101.4% 1) 101.2% 1) 101.1% 1) 100.9% Sodium theoretical 2)100.5% 2) 102.4% 2) 102.3% 2) 101.1% 2) 101.0% 2) 100.2% 2) 101.7% 2)101.0% 2) 101.1% Benzoate Mean: Mean: Mean: Mean: Mean: Mean: Mean:Mean: 101.1% Mean: 101.0% 100.5% 102.1% 102.2% 101.3% 101.1% 100.8%101.5% pH 4.5-5.5 5.05 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Osmolality ≤400mOsm/kg 182 mOsm/kg 186 mOsm/kg 185 mOsm/kg 182 mOsm/kg 186 mOsm/kg 184mOsm/kg 183 mOsm/kg 186 mOsm/kg 187 mOsm/kg Specific Report result1.0077 NR NR NR NR NR NR NR NR Gravity Microbial TAMC: NMT 10² cfu/mL<10 cfu/mL NR NR NR NR NR NR NR NR Limits TCYM: NMT 10¹ cfu/mL <10cfu/mL E. Coli: Absent/mL Absence/mL S. aureus: Absent/mL Absence/mL P.aeruginosa: Absent/mL Absence/mL Salmonella: Absent/10 mL Absence/10 mLB. cepacia: Absent/mL Absence/mL AET Meets acceptance Pass NR NR NR NRNR NR NR NR criteria stated in USP<51> Water Loss Report result NR NR NRNR NR NR NR NR NR *OOS66773

TABLE 4 Stability of 480 mL at 30° C./65% RH 6 month 8 month 9 month 11month Initial Upright Inverted Upright Inverted Upright Inverted UprightInverted Date Samples Apr. 4, 2013 Oct. 4, 2013 Oct. 4, 2013 Dec. 2,2013 Dec. 2, 2013 Jan. 9, 2014 Jan. 9, 2014 Feb. 28, 2014 Feb. 28, 2014Pulled Appearance Clear, colorless Complies Complies Complies CompliesComplies Complies Complies Complies Complies liquid Appearance of 480mL, amber PET Complies Complies Complies Complies Complies CompliesComplies Complies Complies Packaging round bottle; white child resistantcap with induction seal. No visible damage to any of the componentsIdentification Exhibits major peak Complies NR NR NR NR NR NR NR NR ofSotalol HCl for Sotalol; by HPLC Retention time is the same as that ofthe reference standard Identification The spectrum of the Complies NR NRNR NR NR NR NR NR of Sotalol HCl main peak in the by UV samplechromatogram matches the spectrum of the main peak in the standardchromatogram Assay for 90.0%-110.0% of 1) 101.0% 1) 100.7% 1) 100.5% 1)101.8% 1) 102.5% 1) 100.6% 1) 101.5% 1) 102.4% 1) 102.0% Sotalol HCltheoretical 2) 102.1% 2) 100.8% 2) 100.7% 2) 102.3% 2) 103.5% 2) 101.0%2) 100.7% 2) 102.7% 2) 102.3% Mean: Mean: Mean: Mean: Mean: Mean: Mean:Mean: 102.6% Mean: 101.6% 100.8% 100.6% 102.1% 103.0% 100.8% 101.1%102.2% Related Related Compound ND ND ND ND ND ND ND ND ND Substances A:NMT 0.2% Related Compound ND ND ND ND ND ND ND <QL <QL B: NMT 0.2%Related Compound ND ND ND ND ND ND ND ND ND C: NMT 0.2% Unknown RRT0.74: RRT 2.05: RRT 2.05: RRT 2.17: <QL RRT 2.17: <QL RRT 2.10: <QL RRT2.60: RRT 2.14: <QL RRT 2.13: Impurities: NMT 0.14% 0.05% 0.06% RRT2.76: RRT 2.75: RRT 2.61: 0.13% RRT 2.62: <QL 0.05% 0.1% RRT 2.12: <QLRRT 2.10: RRT 2.10: 0.11% 0.11% 0.13% RRT 2.70: <QL RRT 2.91: 0.17%* RRT2.90: 0.05% 0.05% RRT 2.71: <QL RRT 3.04: <QL 0.17%* RRT 2.67: RRT 2.68:RRT 3.02: <QL 0.11% 0.10% RRT 2.79: <QL Total Impurities: 0.14% 0.21%0.21% 0.11% 0.11% 0.13% 0.13% 0.17% 0.22% NMT 2.5% Assay of 80.0-110.0%of 1) 100.0% 1) 102.4% 1) 102.2% 1) 101.3% 1) 101.3% 1) 100.3% 1)102.1% 1) 100.4% 1) 100.8% Sodium theoretical 2) 99.9% 2) 102.9% 2)102.3% 2) 101.4% 2) 101.1% 2) 101.6% 2) 101.6% 2) 100.5% 2) 101.3%Benzoate Mean: Mean: Mean: Mean: Mean: Mean: Mean: Mean: 100.5% Mean:100.0% 102.7% 102.3% 101.4% 101.2% 101.0% 101.9% 101.1% pH 4.5-5.5 5.065.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Osmolality ≤400 mOsm/kg 182 mOsm/kg 186mOsm/kg 184 mOsm/kg 182 mOsm/kg 183 mOsm/kg 183 mOsm/kg 185 mOsm/kg 185mOsm/kg 185 mOsm/kg Specific Report result 1.0076 NR NR NR NR NR NR NRNR Gravity Microbial TAMC: NMT 10² cfu/mL <10 cfu/mL NR NR NR NR NR NRNR NR Limits TCYM: NMT 10¹ cfu/mL <10 cfu/mL E. Coli: Absent/mLAbsence/mL S. aureus: Absent/mL Absence/mL P. aeruginosa: Absent/mLAbsence/mL Salmonella: Absent/10 mL Absence/10 mL B. cepacia: Absent/mLAbsence/mL AET Meets acceptance Pass NR NR NR NR NR NR NR NR criteriastated in USP<51> Water Loss Report result NR NR NR NR NR NR NR NR NR

TABLE 5 Stability of 250 mL at 40° C./75% RH 1 month 3 month InitialUpright Inverted Upright Date Samples Apr. 4, 2013 May 6, 2013 May 6,2013 Jul. 9, 2013 Pulled Appearance Clear, colorless liquid CompliesComplies Complies Complies Appearance of 250 mL, amber PET roundComplies Complies Complies Complies Packaging bottle; white childresistant cap with induction seal. No visible damage to any of thecomponents Identification Exhibits major peak for Complies NR NR NR ofSotalol HCl Sotalol; Retention time is the by HPLC same as that of thereference standard Identification The spectrum of the main Complies NRNR NR of Sotalol HCl peak in the sample by UV chromatogram matches thespectrum of the main peak in the standard chromatogram Assay for90.0%-110.0% of theoretical 1) 101.5% 1) 100.4% 1) 100.7% 1) 100.3%Sotalol HCl 2) 101.4% 2) 100.8% 2) 100.6% 2) 99.9% Mean: Mean: Mean:Mean: 100.1% 101.5% 100.6% 100.7% Related Related Compound A: NMT ND NDND ND Substances 0.2% Related Compound B: NMT ND ND ND ND 0.2% RelatedCompound C: NMT ND ND ND ND 0.2% Unknown Impurities: NMT RRT 0.74: 0.10%ND ND RRT 2.60: 0.15%* 0.1% RRT 2.12: 0.05% Total Impurities: NMT 2.5%0.15% ND ND 0.15% Assay of 80.0-110.0% of theoretical 1) 99.5% 1)100.6% 1) 100.2% 1) 101.7% Sodium 2) 100.1% 2) 100.6% 2) 100.0% 2)102.8% Benzoate Mean: 99.8% Mean: Mean: Mean: 102.3% 100.6% 100.1% pH4.5-5.5 5.04 4.96 4.98 5.0 Osmolality ≤400 mOsm/kg 181 mOsm/kg 185mOsm/kg 185 mOsm/kg 182 mOsm/kg Specific Report result 1.0076 NR NR NRGravity Microbial TAMC: NMT 10² cfu/mL <10 cfu/mL NR NR NR Limits TCYM:NMT 10¹ cfu/mL <10 cfu/mL E. Coli: Absence/mL Absent/mL S. aureus:Absence/mL Absent/mL P. aeruginosa: Absence/mL Absent/mL Salmonella:Absence/10 mL Absent/10 mL B. cepacia: Absence/mL Absent/mL AET Meetsacceptance criteria Pass NR NR NR stated in USP<51> Water Loss Reportresult NR NR NR NR 3 month 6 month Inverted Upright Inverted DateSamples Jul. 9, 2013 Oct. 4, 2013 Oct. 4, 2013 Pulled Appearance Clear,colorless liquid Complies Complies Complies Appearance of 250 mL, amberPET round Complies Complies Complies Packaging bottle; white childresistant cap with induction seal. No visible damage to any of thecomponents Identification Exhibits major peak for NR NR NR of SotalolHCl Sotalol; Retention time is the by HPLC same as that of the referencestandard Identification The spectrum of the main NR NR NR of Sotalol HClpeak in the sample by UV chromatogram matches the spectrum of the mainpeak in the standard chromatogram Assay for 90.0%-110.0% oftheoretical 1) 99.5% 1) 102.2% 1) 101.7% Sotalol HCl 2) 100.0% 2) 102.0%2) 101.3% Mean: 99.8% Mean: 102.1% Mean: 101.5% Related Related CompoundA: NMT ND ND ND Substances 0.2% Related Compound B: NMT ND ND ND 0.2%Related Compound C: NMT ND ND ND 0.2% Unknown Impurities: NMT RRT 2.62:0.15%* RRT 2.62: 0.25%* RRT 2.60: 0.25%* 0.1% Total Impurities: NMT 2.5%0.15% 0.25% 0.25% Assay of 80.0-110.0% of theoretical 1) 102.2% 1)102.5% 1) 102.2% Sodium 2) 102.2% 2) 102.0% 2) 102.3% Benzoate Mean:102.2% Mean: 102.3% Mean: 102.3% pH 4.5-5.5 5.0 5.0 5.0 Osmolality ≤400mOsm/kg 182 mOsm/kg 185 mOsm/kg 184 mOsm/kg Specific Report result NR NRNR Gravity Microbial TAMC: NMT 10² cfu/mL NR NR NR Limits TCYM: NMT 10¹cfu/mL E. Coli: Absence/mL S. aureus: Absence/mL P. aeruginosa:Absence/mL Salmonella: Absence/10 mL B. cepacia: Absence/mL AET Meetsacceptance criteria NR NR NR stated in USP<51> Water Loss Report resultNR NR NR *OOS66773

TABLE 6 Stability of 480 mL at 40° C./75% RH 1 month 3 month InitialUpright Inverted Upright Date Samples Apr. 4, 2013 May 6, May 6, Jul. 9,2013 Pulled 2013 2013 Appearance Clear, colorless liquid CompliesComplies Complies Complies Appearance of 480 mL, amber PET CompliesComplies Complies Complies Packaging round bottle; white child resistantcap with induction seal. No visible damage to any of the componentsIdentification of Exhibits major peak for Complies NR NR NR Sotalol HClby Sotalol; Retention time HPLC is the same as that of the referencestandard Identification of The spectrum of the Complies NR NR NR SotalolHCl by main peak in the sample UV chromatogram matches the spectrum ofthe main peak in the standard chromatogram Assay for 90.0%-110.0% of 1)101.0% 1) 100.8% 1) 100.9% 1) 101.2% Sotalol HCl theoretical 2) 102.1%2) 100.6% 2) 101.0% 2) 100.9% Mean: Mean: Mean: Mean: 101.6% 100.7%101.0% 101.1% Related Related Compound A: ND ND ND ND Substances NMT0.2% Related Compound B: ND ND ND ND NMT 0.2% Related Compound C: ND NDND ND NMT 0.2% Unknown Impurities: RRT 0.74: ND ND RRT 2.42: NMT 0.1%0.14% 0.13%* RRT 2.12: <QL Total Impurities: NMT 0.14% ND ND 0.13% 2.5%Assay of 80.0-110.0% of 1) 100.0% 1) 101.2% 1) 100.8% 1) 102.4% Sodiumtheoretical 2) 99.9% 2) 100.6% 2) 100.4% 2) 102.3% Benzoate Mean: Mean:Mean: Mean: 100.0% 100.9% 100.6% 102.4% pH 4.5-5.5 5.06 4.96 4.95 5.0Osmolality ≤400 mOsm/kg 182 mOsm/kg 185 mOsm/kg 185 mOsm/kg 182 mOsm/kgSpecific Gravity Report result 1.0076 NR NR NR Microbial TAMC: NMT 10²cfu/mL <10 cfu/mL NR NR NR Limits TCYM: NMT 10¹ cfu/mL <10 cfu/mL E.Coli: Absence/mL Absent/mL S. aureus: Absence/mL Absent/mL P.aeruginosa: Absent/mL Absence/mL Salmonella: Absent/10 mL Absence/10 mLB. cepacia: Absence/mL Absent/mL AET Meets acceptance Pass NR NR NRcriteria stated in USP<51> Water Loss Report result NR NR NR NR 3 month6 month Inverted Upright Inverted Date Samples Jul. 9, 2013 Oct. 4, 2013Oct. 4, 2013 Pulled Appearance Clear, colorless liquid Complies CompliesComplies Appearance of 480 mL, amber PET Complies Complies CompliesPackaging round bottle; white child resistant cap with induction seal.No visible damage to any of the components Identification of Exhibitsmajor peak for NR NR NR Sotalol HCl by Sotalol; Retention time HPLC isthe same as that of the reference standard Identification of Thespectrum of the NR NR NR Sotalol HCl by main peak in the sample UVchromatogram matches the spectrum of the main peak in the standardchromatogram Assay for 90.0%-110.0% of 1) 101.6% 1) 102.7% 1) 102.2%Sotalol HCl theoretical 2) 101.8% 2) 102.5% 2) 101.9% Mean: Mean: Mean:101.7% 102.6% 102.1% Related Related Compound A: ND ND ND Substances NMT0.2% Related Compound B: ND ND ND NMT 0.2% Related Compound C: ND ND NDNMT 0.2% Unknown Impurities: RRT 2.41: RRT 2.58: RRT 2.59: NMT 0.1%0.13%* 0.25%* 0.24%* Total Impurities: NMT 0.13% 0.25% 0.24% 2.5% Assayof 80.0-110.0% of 1) 102.7% 1) 102.3% 1) 101.9% Sodium theoretical 2)102.1% 2) 102.3% 2) 100.7% Benzoate Mean: Mean: Mean: 102.4% 102.3%101.3% pH 4.5-5.5 5.0 5.0 5.0 Osmolality ≤400 mOsm/kg 182 mOsm/kg 186mOsm/kg 185 mOsm/kg Specific Gravity Report result NR NR NR MicrobialTAMC: NMT 10² cfu/mL NR NR NR Limits TCYM: NMT 10¹ cfu/mL E. Coli:Absence/mL S. aureus: Absence/mL P. aeruginosa: Absence/mL Salmonella:Absence/10 mL B. cepacia: Absence/mL AET Meets acceptance NR NR NRcriteria stated in USP<51> Water Loss Report result NR NR NR *OOS66773

A photostability study was conducted under ICH light conditions onSotalol Hydrochloride Oral Solution batch MFYN packaged in 250 mL and480 mL packaging configuration. The samples were exposed tophotostability conditions as described in ICH guideline Q1B “StabilityTesting: Photostability Testing of New Drug Substances and Products,Option 2.” The samples were exposed to light in the proposed commercialpackaging and in the proposed commercial packaging wrapped in aluminumfoil (control sample). The results are shown below:

Photostability Results for Sotalol Hydrochloride Oral Solution BatchMHBV Batch MHBV Batch MHBP Batch MHBP Test Light Exposed Light ControlLight Exposed Light Control Assay for 102.0% 101.8% 102.0% 102.6%Sotalol HCL Related None Detected None Detected None Detected NoneDetected Compound A (NMT 0.2%) Related None Detected None Detected NoneDetected None Detected Compound B (NMT 0.2%) Related None Detected NoneDetected None Detected None Detected Compound C (NMT 0.2%) TotalImpurities 0.0 0.0 0.0 0.0 (NMT 0.2%) Assay for 100.8% 102.7% 103.6%101.4% Sodium Benzoate pH 5.0 5.0 5.0 5.0 Osmolality 174 174 174 174(mOsm/kg) Specific Gravity 1.00645 1.00702 1.00676 1.00676

As the differences between the results for the light exposed and thecontrol samples were insignificant, the Sotalol Hydrochloride OralSolution, 5 mg/mL, was considered to be protected from light whencontained in its primary packaging. The results met shelf life criteriafor the individual tests. The Sotalol HCl assay results did not differbetween the dark control and the light exposed samples. The assay forrelated substances demonstrated no significant degradation in both thedark control and light exposed samples, with no related substancesresults above the acceptance criteria of not more than (NMT) 0.1%individual unidentified impurities and no detected known relatedcompounds. There were no impurity peaks detected in the samples abovethe reporting limit of 0.05%. Results for assay for preservative (sodiumbenzoate) did not differ between the dark control and light exposedsamples. Osmolality, specific gravity, and pH results did not differbetween the dark control and light exposed samples.

Results were within specification for all testing parameters (sotalolHCl assay, sodium benzoateassay, pH, osmolality, appearance, ID, waterloss, and related substances A, B, & C). For unknown impurities,although stable at room temperature (25° C./60% RH) storage, drugproduct stability data show an additional impurity in the range RRT2.57-2.81 that has presented above the ICH Q3B(R2) reporting threshold(0.1%) at accelerated storage conditions and at or near the 0.1% limitat the 30° C./65% RH condition. However, this impurity remains at orbelow the Quantification Limit at room temperature conditions.

Shelf-life Specifications and Analytical Tests Test Limit MethodAppearance Clear, colorless liquid Visual inspection Appearance of 480mL, amber PET round bottle; white child resistant Visual inspectionpackaging cap with induction seal. No visible damage to any of thecomponents. 250 mL, amber PET round bottle; white child resistant capwith induction seal. No visible damage to any of the components.Identification of Exhibits major peak for Sotalol. Retention time is theCTMLP-3056 Sotalol HC1 by HPLC same as that of reference standard. (T =0 only) Identification of The spectrum of the main peak in the sampleCTMLP-3056 Sotalol HC1 by UV chromatogram matches the spectrum of themain peak (T = 0 only) in the standard chromatogram. Assay for SotalolHC1 90.0%-410.0% of theoretical CTMLP-3056 Related substances RelatedCompound A: NMT 0.2%* CTMLP-3056 Related Compound B: NMT 0.2% RelatedCompound C: NMT 0.2%* Unidentified impurity: NMT 0.1% Total impurities:NMT 2.5% Assay for Sodium 80.0%-110.0% of theoretical CTMLP-3057benzoate pH 4.5-5.5 USP <791> Osmolality ≤400 mOsm/kg USP <785> Specificgravity Report result USP <841> (T = 0 only) Method 1

Analytical Tests

I) Identification of Sotalol HCl in Oral Solution by HPLC and UV (StudyCTMLP-3056)

Equipment and Materials

-   -   HPLC system with UV detector and data acquisition    -   Balance, capable of accurately weighing to 0.1 mg    -   Sotalol Hydrochloride Reference Standard    -   Sotalol HCI Related Substance A, (RS1)    -   Sotalol HCI Related Substance B, (RS2)    -   Sotalol HCI Related Substance C, (RS3)    -   Column: Waters 1-1-Bondapack 300 mm×3.9 mm C18 (L 1)    -   Acetonitrile (HPLC Grade or equivalent)    -   Monobasic Potassium Phosphate (HPLC Grade or equivalent)    -   Miscellaneous glassware    -   0.45 μm nylon membrane filter    -   Deionized water    -   HPLC vial

Procedure

Preparation of Mobile Phase and Diluent—Make appropriate adjustment forlarger or smaller final volume requirement.

-   -   1) Preparation of Phosphate Buffer Solution—For the preparation        of one liter of Phosphate Buffer solution, dissolve 6.8 g of        Monobasic Potassium Phosphate in 1000 ml D.I. water and mix        well. Filter through 0.45 μm nylon membrane filter.    -   2) Preparation of Mobile Phase A—For the preparation of one        liter of mobile phase, combine 950 ml of Phosphate Buffer        solution with 50 ml of Acetonitrile. Mix well and degas.    -   3) Preparation of Mobile Phase B—100% acetonitrile, degas.    -   4) Preparation of Diluent—Combine 800 ml of D.I. water with 200        ml of Acetonitrile. Mix well.

Preparation of Standard Solution—Note: The working standard solution isstable up to 3 days at room temperature and 2-8° C.

-   -   1) Preparation of Working Standard Solution—Accurately weigh 20        mg of Sotalol Hydrochloride reference standard to a 100 ml        volumetric flask. Dissolve and dilute to volume with diluent.        Mix well. Concentration of Sotalol Hydrochloride: −200 μg/ml    -   2) Preparation of Check Standard Solution—Same as Preparation of        Working Standard Solution.    -   3) Preparation of Resolution Solution

Note: The resolution solutions should be stored under refrigeration. Thesolution can be used as long as RSA, RSB and RSC peaks can be clearlyidentified in the resolution solution and all the system suitabilityparameters are met.

Accurately weigh and transfer 10±1 mg each of RS1 to RS3 referencematerial into three separate 500 ml volumetric flasks. Add approximately350 ml of diluent into each flask to dissolve (sonicate 5 mins ifnecessary). Allow to cool to room temperature. Dilute to volume withdiluent and mix well.

Accurately weigh 20 mg of Sotalol Hydrochloride reference standard intoa 100 mL volumetric flask, add 5.0 ml of each known related substancestock standard solution. Dilute to volume with diluent and mix well.

Concentration of Sotalol HCI˜200 μg/ml.

Concentration of each known related substance˜1 μg/ml

Preparation of Sample Solution

Note: Prepare sample solution in duplicate. The sample solutions arestable up to 3 days at room temperature and 2-8° C. Pipette 4.0 ml of asample solution into a 100 ml volumetric flask. Dissolve and dilute tovolume with diluent. Mix well. Filter a portion of the solution througha 0.45 μm Nylon syringe filters discarding the initial 3 ml of filtrate.

Concentration of Sotalol Hydrochloride: ˜200 μg/ml

Instrument Parameters

-   -   Column: Waters μ-Bondapack 300 mm×3.9 mm C18 (L 1)    -   Column Temperature: Ambient    -   Detection: UV@220 nm    -   Injection Volume: 35 μL    -   Flow Rate: 1.5 mL/min    -   Run Time: 45 minutes    -   Mobile Phase A: Phosphate Buffer:ACN=950:50 (v/v)    -   Mobile Phase B: 100% CAN

Gradient Table: Time (Min) A % B % 0.0 100 0 10.0 92 8 13.0 85 15 20.040 60 25.0 35 65 30.0 35 65 30.1 100 0 40.0 100 0

Injection Procedure

-   -   1) Make one injection of the diluent.    -   2) Make one injection of resolution solution    -   3) Make five consecutive injections of the working standard        solution    -   4) Make one injections of the check standard solution    -   5) Make one injection of each sample solution    -   6) Make one injection of the working standard solution after        every six sample solution injections and at the end of the        sequence run

The following system suitability criteria must be met.

The working standard solution will be consecutively injected five times.The RSD of the Sotalol Hydrochloride peak areas from the fiveconsecutive injections of the working standard solution should be ≤2.0%.

Calculate the USP tailing factor, T, from,T=W _(0.05)/2ƒ

Where, W_(0.05) is the peak width of Sotalol Hydrochloride peak at 5% ofthe peak height from the baseline and ƒ is the distance from the peakmaximum to the leading edge of the peak. The USP tailing factor ofSotalol Hydrochloride peak in the first injection of the workingstandard solution should be ≤2.0.

The Number of Theoretical Plates per column, N, can be calculated asfollows:N=16(t/W)²

Where t is the retention time of Sotalol Hydrochloride peak and W is thepeak width of Sotalol Hydrochloride peak, obtained by extrapolating therelatively straight sides of peak to the base line. The Number ofTheoretical Plates per column for Sotalol Hydrochloride peak in thefirst injection of the Working standard solution should be ≥2000.

Calculate the resolution factor (R) between all successive and adjacentpeaks from the resolution solution as follows:

$R = \frac{2\left( {t_{n + 1} - t_{n}} \right)}{W_{n + 1} + W_{n}}$

Where,

t_(n)=Retention time of peak n

t_(n+1)=Retention time of peak n+1

W_(n)=Peak width of peak n

W_(n+1)=Peak width of peak n+1

The resolution factor between all successive and adjacent peaks in theresolution solution should be ≥2.0.

Make one injection of the check standard solution into HPLC system foranalysis.

Calculate the % recovery of Sotalol Hydrochloride in the check standardas follows.% Recovery=(A _(CK) /Wt _(CK))×(Wt _(WSTD) /A _(WSTD)×100%

Where,

A_(CK)=Peak area of Sotalol Hydrochloride from the check standardsolution

A_(WSTD)=Average peak area of Sotalol Hydrochloride from five injectionsof the working standard solution

Wt_(CK)=Weight of Sotalol Hydrochloride in the preparation of the checkstandard solution

Wt_(WSTD)=Weight of Sotalol Hydrochloride used in the preparation of theworking standard solution

The % recovery of Sotalol Hydrochloride of the check standard solutionshould be within 98.0% to 102.0%.

System Drift

Make one injection of the working standard solution after injection ofevery six sample injections and at the end of the sequence run.Calculate the % recovery of Sotalol Hydrochloride from each system driftinjections as follows:% Recovery=(A _(SCK) /A _(WSTD))×100

Where,

A_(SCK)(=Peak area of Sotalol Hydrochloride from the system driftinjection of the working standard solution

A_(WSTD)=Average peak area of Sotalol Hydrochloride from the first fivesystem suitability injections of the working standard solution

For system drift, the % recovery of Sotalol Hydrochloride from everysystem drift injection throughout the sequence run should be within98.0% to 102.0%.

Calculation and Results

% LC of Sotalol HCI can be calculated as follows:% LC=(A _(spl) /A _(std))×W _(std) ×P_(std)×(DF_(spl)/DF_(std))×(1/V×LC)×100%

Impurities can be calculated as follows:% RS=(A _(RS) /A _(std))×W _(std) ×P_(std)×(DF_(spl)/DF_(std))×(RRF/V×LC)×100%

Where:

A_(spl)=Peak Area of Sotalol Hydrochloride obtained from SamplePreparation

A_(std)=Average Peak Area of Sotalol Hydrochloride obtained from fiveinjections of Working Standard Solution

W_(std)=Weight of Sotalol Hydrochloride Reference Standard (mg)

P_(std)=Potency of Sotalol Hydrochloride Reference Standard

DF_(std)=Dilution Factor of the Working Standard Preparation

DF_(spl)=Dilution Factor of the Sample Preparation

LC=Label Claim of Sotalol Hydrochloride

V=Sample Volume (4.0 ml)

RRF=Relative Response Factor (Known Impurities of RSA=1.33; RSB=0.70;RSC=0.99; all unknown: 1.00)

Report the % LC of Sotalol HCI to one decimal place

Report % Related substances to two decimal places >0.05%.

The DL/QL and RRF values are listed below:

Related Substance DL QL RRF Unknown related substance 0.02% 0.05% 1.0(based on Sotalol HCl) RS_(A) 0.02% 0.05% 1.33 RS_(B) 0.02% 0.05% 0.7RS_(C) 0.02% 0.05% .99

If the related substance is present below the QL but above DL report as<QL.

If the related substance is present at <DL report as not detected

II) Assay for Sodium Benzoate (Study CTMLP-3057)

Equipment and Materials

-   -   HPLC system with UV detector and data acquisition    -   Balance, capable of accurately weighing to 0.1 mg    -   pH meter    -   Sodium Benzoate Reference Standard    -   Column: Agilent Zorbax C18, 5 μm 4.6 mm×250 mm    -   HPLC vial    -   Acetonitrile (HPLC Grade or equivalent)    -   Ammonium Acetate (HPLC Grade or equivalent)    -   Glacial Acetic Acid (HPLC Grade or equivalent)    -   Miscellaneous glassware    -   0.45 um nylon membrane filter    -   Deionized water

Procedure

-   -   1) Preparation of Mobile Phase and Diluent—Make appropriate        adjustment for larger or smaller final volume requirement.    -   2) Preparation of Acetate Buffer Solution—For the preparation of        one liter of Acetate Buffer Solution, dissolve 0.30 g of        Ammonium Acetate in about 900 ml of 0.1. water. Adjust the pH to        4.2.t 0.05 with Glacial Acetic Acid and dilute with D.I. water        to 1000 ml, and mix well. Filter through 0.45 μg nylon membrane        filter.    -   3) Preparation of Mobile Phase—For the preparation of one liter        of mobile phase, combine 900 ml of Acetate Buffer (pH=4.2) with        125 ml of Acetonitrile. Mix well and degas before use.    -   4) Preparation of Diluent—The same preparation as Preparation of        Mobile Phase.

Preparation of Standard Solution—

-   -   1) Preparation of Stock Standard Solution        -   Accurately weigh 50 mg of Sodium Benzoate reference            standard, and transfer to a 50 ml volumetric flask. Dissolve            and dilute to volume with diluent. Mix well. Concentration            of Sodium Benzoate: 1000 μg/ml.    -   2) Preparation of Working Standard Solution        -   Note: The working standard solution is stable up to 4 days            at room temperature and 2-8° C. Pipette 5.0 ml of the stock            standard solution to a 100 ml volumetric flask. Dilute to            volume with diluent and mix. Concentration of Sodium            Benzoate: ˜50 μg/ml    -   3) Preparation of Check Standard Solution        -   Repeat section Preparation of Stock Standard Solution and            Preparation of Working Standard Solution.    -   4) Preparation of Sample Solution        -   Note: Prepare sample solution in duplicate. The sample            solution is stable up to 3 days at room temperature and 2-8°            C.

For sample containing 2.5 mg/ml Sodium Benzoate Pipette 10.0 ml of asample solution into a 100 ml volumetric flask. Dissolve and dilute tovolume with diluent. Mix well. Pipette 10.0 ml of the solution to a 50mL volumetric flask and dilute to volume with diluent. Mix well.

Concentration of Sodium Benzoate: ˜50 μg/mL

For sample containing 2.0 mg/ml Sodium Benzoate

Pipette 12.0 ml of a sample solution Into a 100 ml volumetric flask.Dissolve and dilute to volume with diluent. Mix well. Pipette 10.0 ml ofthe solution to a 50 mL volumectric flask and dilute to volume withdiluent. Mix well.

Concentration of Sodium Benzoate: ˜48 μg/ml

Instrument Parameters

-   -   Column: Agilent Zorbax C18, 4.6 mm×250 mm, 5 μm    -   Column Temperature: Ambient    -   Detection: UV@225 nm    -   Injection Volume: 5˜    -   Flow Rate: 1.5 mL/min    -   RunTime: 22 minutes    -   Mobile Phase: Acetate Buffer:ACN=900:125 (v/v)

Injection Procedure

-   -   1) Make one injection of the diluent.    -   2) Make five consecutive injections of the working standard        solution    -   3) Make one injections of the check standard solution    -   4) Make one injection of each sample solution    -   5) Make one injection of the working standard solution after        every six sample solution Injections and at the end of the        sequence run

The following system suitability criteria must be met.

The working standard solution will be consecutively injected five times.The RSD of the Sodium Benzoate peak areas from the five consecutiveinjections of the working standard solution should be ≤2.0%.

Calculate the USP tailing factor, T, from,T=W _(0.05)/2ƒ

Where, W_(0.05) is the peak width of Sodium Benzoate peak at 5% of thepeak height from the baseline and ƒ is the distance from the peakmaximum to the leading edge of the peak. The USP tailing factor ofSodium Benzoate peak in the first injection of the working standardsolution should be ≤2.0.

The Number of Theoretical Plates per column, N, can be calculated asfollows:N=16(t/W)²

Where t is the retention time of Sodium Benzoate peak and W is the peakwidth of Sodium Benzoate peak, obtained by extrapolating the relativelystraight sides of peak to the base line. The Number of TheoreticalPlates per column for Sodium Benzoate peak in the first injection of theWorking standard solution should be ≥2000.

Make one injection of the check standard solution into HPLC system foranalysis. Calculate the % recovery of Sodium Benzoate in the checkstandard as follows.% Recovery=(A _(CK) /Wt _(CK))×(Wt _(WSTD) /A _(WSTD))×100%

Where,

A_(CK)=Peak area of Sodium Benzoate from the check standard solution

A_(WSTD)=Average peak area of Sodium Benzoate from five injections ofthe working standard solution

Wt_(CK)=Weight of Sodium Benzoate in the preparation of the checkstandard solution

Wt_(WSTD)=Weight of Sodium Benzoate used in the preparation of theworking standard solution

The % recovery of Sodium Benzoate of the check standard solution shouldbe within 98.0% to 102.0%.

System Drift

Make one injection of the working standard solution after injection ofevery six sample injections and at the end of the sequence run.Calculate the % recovery of Sodium Benzoate from each system driftinjections as follows:% Recovery=(A _(SCK) /A _(WSTD))×100

Where,

A_(SCK)(=Peak area of Sodium Benzoate from the system drift injection ofthe working standard solution

A_(WSTD)=Average peak area of Sodium Benzoate from the first five systemsuitability injections of the working standard solution

For system drift, the % recovery of Sodium Benzoate from every systemdrift injection throughout the sequence run should be within 98.0% to102.0%.

Calculation and Results

The results can be calculated as follows:% Sodium Benzoate=(A _(spl) /A _(std))×W _(std) ×P_(std)×(DF_(spl)/DF_(std))×(1/LC)×100%

Where:

A_(spl)=Peak Area of Sodium Benzoate obtained from Sample Preparation

A_(std)=Average Peak Area of Sodium Benzoate obtained from fiveinjections of Working Standard Solution

W_(std)=Weight of Sodium Benzoate Reference Standard (mg)

P_(std)=Potency of Sodium Benzoate Reference Standard

DF_(std)=Dilution Factor of the Working Standard Preparation

DF_(spl)=Dilution Factor of the Sample Preparation

LC=Label Claim of Sodium Benzoate (2.5 mg/mL or 2.0 mg/mL)

Report result to one decimal.

We claim:
 1. An oral solution comprising sotalol hydrochloride, whereinthe solution has an osmolality in the range of about 50 mOsm/kg to about400 mOsm/kg.
 2. The oral solution of claim 1, wherein the solution isfree of polymers.
 3. The oral solution of claim 1, wherein the solutionhas a pH between about 3 and about
 7. 4. The oral solution of claim 1,wherein the solution has an osmolality in the range of about 200 mOsm/kgto about 300 mOsm/kg.
 5. The oral solution of claim 1, wherein sotalolhydrochloride is present in an amount of about 5 mg/mL or about 0.5% byweight.
 6. The oral solution of claim 1, wherein the sotalolhydrochloride is present in an amount from about 0.2% to about 0.8% byweight.
 7. The oral solution of claim 1, further comprising an excipientselected from the group consisting of buffering substances,preservatives, high potency sweeteners and flavoring agents, orcombinations thereof.
 8. The oral solution of claim 7, wherein thebuffering substance is sodium citrate or citric acid, alone or incombination.
 9. The oral solution of claim 7, wherein the preservativeis sodium benzoate.
 10. The oral solution of claim 7, wherein the highpotency sweetener is sucralose.
 11. The oral solution of claim 7,wherein the flavoring agent is artificial grape flavor.
 12. The oralsolution of claim 1, further comprising water in an amount of about 95%to about 99% by weight.
 13. A method of delaying recurrence of atrialfibrillation/atrial flutter in a host in need thereof, comprisingadministering an effective amount of an oral solution comprising sotalolhydrochloride, wherein the solution has an osmolality in the range ofabout 50 mOsm/kg to about 400 mOsm/kg.
 14. A method of treatingdocumented life-threatening ventricular arrhythmias in a host in needthereof, comprising administering an effective amount of an oralsolution comprising sotalol hydrochloride, wherein the solution has anosmolality in the range of about 50 mOsm/kg to about 400 mOsm/kg. 15.The oral solution of claim 1, wherein the solution is stored at atemperature between about 25° C. and about 40° C. and a relativehumidity of between about 60% and about 75%.
 16. The method of claim 13wherein the oral solution is stored at a temperature between about 25°C. and about 40° C. and a relative humidity of between about 60% andabout 75%.
 17. The method of claim 13, wherein a 80 mg daily dose of theoral solution is administered.
 18. The method of claim 13, whereinadministration of the oral solution occurs once, twice or three times aday.
 19. The method of claim 13, wherein the oral solution compriseswater in an amount of about 95% to about 99% by weight and sotalolhydrochloride in an amount from about 0.2% to about 8% by weight. 20.The method of claim 14, wherein a 80 mg daily dose is administered. 21.The method of claim 14, wherein administration occurs once, twice orthree times a day.
 22. The method of claim 14, wherein the oral solutioncomprises water in an amount of about 95% to about 99% by weight andsotalol hydrochloride in an amount from about 0.2% to about 8% byweight.